(indolymethyl) malonate compound

ABSTRACT

6-(Trifluoromethyl)tryptophane, useful as a non-nutritive sweetening agent and also useful in the synthesis of a corresponding pyrrolnitrin derivative; and intermediates useful in the synthesis of 6-(trifluoromethyl)tryptophane.

United States Patent Kornfeld 1 July 11,1972

(INDOLYMETHYL) MALONATE COMPOUND Inventor: Edmund Carl Kornfeld,Indianapolis, Ind.

Assignee: Eli Lilly and Company, Indianapolis, Ind.

Filed: June 11, 1970 Appl. No.: 57,872

Related U.S. Application Data Division of Ser. No. 719,666, April 8,I968, Pat. No. 3,535,336, Division of Ser. No. 57,873, June 11, 1970.

U.S. Cl ..260/326.l4 T Int. Cl. ..C07d 27/60 Field of Search ..260/326.14 T [56] References Cited UNITED STATES PATENTS 2,847,420 8/1958 Weeleet al ..260/326.l4 T

Primary Examiner-Alex Mazel Assistant Examiner-Joseph A. NarcavageAttorney-Everet F. Smith and Kathleen R. Schmoyer 57 ABSTRACT 1 Claim,No Drawings (INDOLYMETHYL) MALONATE COMPOUND CROSS REFERENCE TO RELATEDAPPLICATIONS This application is one of two divisional applications ofmy copending application Ser. No. 719,666, filed Apr. 8, 1968, sinceissued as U.S. Pat. No. 3,535,336. The other divisional application isSer. No. 57,873 filed even date herewith.

DETAILED DESCRIPTION OF THE INVENTION As set forth hereinabove, thepresent invention is directed to 6-(trifluoromethyl)tryptophane, acompound having the following structural formula:

- useful in the synthesis of a corresponding pyrrolnitrin derivative.The compound is prepared by the following reaction sequence:

NHCHO NHz Thus, 6-trifiuoromethyl)indole is subjected to a Mannichreaction to obtain 3-(diethylaminomethyl)-6- (trifluoromethyl)indole,which is then condensed with diethyl formamidomalonate to obtain thecorresponding diethyl ([6-(trifluoromethyl)-3-indolyl1methyl)forrnamidoma1onate. Hydrolysis anddecarboxylation produce the desired 6- (trifluoromethyl)tryptophane.

In another aspect, the present invention is directed to 3-(diethylaminomethyl)-6-(trifiuoromethyl)indole and diethyl([6-(trifluoromethyl)-3-indolyl]methyl)formamidomalonate, intermediatesuseful in the synthesis of 6- (trifluoromethyl)tryptophane.

6-(Trifluoromethyl)tryptophane has an asymmetric carbon atom; butresolution of the racemic mixture is not necessary, the mixture itselfbeing useful for the purposes of the present invention. However, onlythe d-enantiomorph is active as a non-nutritive sweetener. When for anyreason it is desired to employ one enantiomorph, resolution of theracemic mixture can be achieved in procedures known in the prior art forthe resolution of unsubstituted tryptophane. Three such procedures arediscussed and exemplified in detail in Chemistry of the Amino Acids,Greenstein et al., Vol. 3, page 2,341 and following (John Wiley andSons, Inc., New York [1961]); particular attention is directed to thefirst two of these (illustrative procedure 39-5 and illustrativeprocedure 39-6).

The preparation of 6-(trifluoromethyl)tryptophane is illustrated by thefollowing examples.

EXAMPLE 1 0 the solution was poured into 360 ml. of 2N sodium hydroxide,

and the desired 3-(diethylaminomethyl )-6- (trifluoromethyl)indoleproduct extracted with ether. The extract was dried, and solvent removedby distillation to separate the product, which was an oil.

EXAMPLE 2 Diethyl ([6-(trifluoromethyl)-3-indolyl]methyl)formamidomalonate 3-(Diethylaminomethyl)-6-(trifluoromethyl)indole (12.5 grams;0.046 mole), prepared as described in the foregoing example, and diethylformamidomalonate (9.4 grams; 0.041 mole) were mixed in 31 ml. oftoluene. Thereafter, 0.76 gram of powdered potassium hydroxide wasadded. The resulting mixture was refluxed, while bubbling in nitrogen,for 1.5 hours. It was then cooled, resulting in precipitation of thediethyl ([6-(trifluoromethyl )-3-indolyl]methyl)formamid omalonateproduct, which was separated by filtration and washed with water. Aportion of the separated product was recrystallized from ethanol, andthe recrystallized portion found to melt at 1825 C.

Analysis, Calc. for c u r u o C, 53.99; H, 4.87; N, 6.73.

Found: C, 53.99; H, 4.78; N, 6.99.

EXAMPLE 3 6-(Trifiuoromethyl)tryptophane A solution of diethyl([6-(trifiuoromethyl)-3-indolyl]- methyl)formamidomalonate (55.3 grams;0.138 mole) in 330 ml. of 1.5N hydrochloric acid, ml. of glacial aceticacid, and 50 ml. of ethanol was refluxed for 17 hours. The solution wasthen concentrated under vacuum, the residue neutralized. with ammoniumhydroxide, and the resulting 6- (trifiuoromethyl)tryptophane productseparated by filtration. The separated product was washed with water andethanol, and a sample thereof recrystallized from acetic acid. Therecrystallized portion melted at 267-70 C. (dec.).

Analysis, Calc. for C I-I F N O C, 52.94; H, 4.07; N, 10.29.

Found: C, 52.66; H, 4.22; N, 10.32.

As noted above, 6-(trifluoromethyl)tryptophane is useful as anon-nutritive sweetener, the compound being non-toxic to animals atrates at which it contributes a sweet taste. v

For this application, the compound can be employed as such; but it isalso possible to employ the compound as its nontoxic physiologicallyacceptable salt. The type or identity of salt is not critical exceptthat it be non-toxic and physiologically acceptable; for the purposes ofthe present description, a

non-toxic salt is one of which the toxicity is not materially greaterthan that of the compound from which it is derived. Suitable alkalinesalts are the ammonium, sodium, potassium, calcium and magnesium salts.Of these, the sodium and calcium salts are preferred. Acid saltformation occurs at the amino nitrogen atom, the ring nitrogen atombeing only weakly basic. The identity of the acid salt forming moiety isnot critical, although it is necessary that the acid be a strong acid,that is, an acid having a pH of, numerically, below about 2, at aconcentration of 0.1N. Suitable strong acids are hydrochloric,hydrobromic, hydriodic, sulfuric, and the like. Salts are prepared inaccordance with known procedures comprising the reaction of the compoundwith a selected acid or base.

Generally, for the sweetening application of the compound or its salt, aconcentration of about 0.075 percent by weight of the compound inliquids, foods, or the like gives a sweetening effect comparable to thatof a 10 percent concentration of sucrose or to that of the standardnon-nutritive sweetening combination of 0.01 percent of sodium saccharinand 0.1 percent of sodium cyclamate. Concentrations of less or more than0075 can be used where the item to be sweetened calls for a lesser orgreater degree of sweetness than that of a 10 percent concentration ofsucrose. The compound can be used alone, or it can be combined withother known sweetening agents, most notably, sodium saccharin or sodiumcyclamate, in which case smaller amounts of the6-(trifluoromethyl)tryptophane suffice. ln representative operations,di-6- (trifluoromethyl)tryptophane was evaluated alone and incombination with sodium saccharin. Comparison was made with a standardsweetening solution of 0.1 percent sodium cyclamate and 0.01 percentsodium saccharin (which standard sweetening solution is also equivalentto a 10 percent solution of sucrose). The pH of all solutions was 6.7.Those solutions having a sweetness comparable to the standard are setforth in the following table.

Percent of dl-6-(trifluoro- Percent of Sodium In regard to the utilityof 6-(trifluoromethyl)tryptophane as 5 an intermediate in the productionof a corresponding pyrrolnitrin derivative, the6-(trifluoromethyl)tryptophane is added to a fermentation broth of thesame type used for the production of the unsubstituted antibioticpyrrolnitrin (Journal of Antibiotics, Series A, Vol. 18, page 211[1965]). Addition of the fi-(trifluoromethyl)tryptophane results in theproduction of a modified pyrrolnitrin antibiotic of the followingformulae:

([6-(trifluoromethyl)-3-indolyl]methyl)for- $273 3? UNITED STATES PATENT@FFEQEW QER'HWEATE @E QOBFREMWN Patent No. 5,676, 68 Dated J ly 11,1.972

Invntofls) Edmund Carl Kornfeld It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

In reference [5h] the title "(INDOLYME'I'HYL)MALONATE COMPOUND" shouldread (INDOLYLMETHYL)MAL'ONATE COMPOUND I In column 1, line about 57, thepart of the formula which reads "CH(COOEt) should read as follows: v

NHCHOV In column 5, line 1 4-, di-6"' should read 'dl-6- I Signed andsealed this 29th -day of May 1973.

(SEAL) Attest:

EDWARD MrPLETCHER JR. ROBERT 'GOTTSCHALK Attesting Officer Commissioner.of Patents

